Pharmacological research最新文献_第3页

IUPHAR review: From foe to friend: Repurposing glucagon to treat obesity and type 2 diabetes IUPHAR综述：从敌人到朋友：胰高血糖素用于治疗肥胖和2型糖尿病。

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2026-01-01 DOI: 10.1016/j.phrs.2025.108077

Andrew J. Elmendorf , Mostafa Yousefian , Il-Man Kim , J. Andrew Hardaway , Kirk Habegger , Jonathan N. Flak

The epidemics of metabolic disease, in the form of obesity and type 2 diabetes, are a growing public health concern. However, incretin-based therapeutics have transformed our ability to address these diseases. While this current generation of incretin analogues show weight regain upon cessation of treatment, the amount of which can depend on the treatment and patient, iterative advancements may improve weight loss durability in the long term. In this review, we discuss the development of glucagon like peptide-1 receptor (GLP-1R) agonists and GLP-1R/ glucose-dependent insulinotropic polypeptide receptor (GIPR) co-agonists, and how future generations will leverage this strategy. We focus our review on glucagon receptor (GCGR) agonism, which has recently been combined with both GLP-1R and GLP-1R/GIPR agonism to generate dual (e.g. survodutide, cotatutide, mazdutide, etc) and triple agonists (e.g. retatrutide, etc) for improved body weight loss via energy expenditure stimulation. We rely on largely pre-clinical evidence for action because clinical data is extremely limited for GCGR agonism. Herein, we review mechanisms by which glucagon receptor agonists act to increase energy expenditure. Finally, we discuss future improvements to incretin-based therapeutics, and how they can include strategies that target the GCGR. The purpose of this review is to discuss mechanisms by which GCGR agonism can reduce body weight and put them in the context of the combination with incretin receptor agonists. Mechanistic data has only currently been evaluated in preclinical rodent models and evidence for similar processes in humans is limited. We also provide perspectives about how treatments can improve for future advancement of obesity treatment.

以肥胖和2型糖尿病为形式的代谢性疾病的流行是一个日益严重的公共卫生问题。然而，以肠促胰岛素为基础的疗法已经改变了我们治疗这些疾病的能力。虽然目前这一代肠促胰岛素类似物在停止治疗后会显示体重恢复，其数量取决于治疗和患者，但从长远来看，迭代的进展可能会提高减肥的持久性。在这篇综述中，我们讨论了胰高血糖素样肽-1受体（GLP-1R）激动剂和GLP-1R/葡萄糖依赖性胰岛素性多肽受体（GIPR）共激动剂的发展，以及后代如何利用这一策略。我们重点回顾了胰高血糖素受体（GCGR）激动剂，它最近与GLP-1R和GLP-1R/GIPR激动剂联合产生双重激动剂（如生存肽、克托肽、玛兹肽等）和三重激动剂（如利特鲁肽等），通过能量消耗刺激改善体重减轻。我们主要依靠临床前证据，因为GCGR激动作用的临床数据极其有限。在此，我们回顾了胰高血糖素受体激动剂增加能量消耗的机制。最后，我们讨论了未来以肠促胰岛素为基础的治疗方法的改进，以及它们如何包括针对GCGR的策略。本综述的目的是讨论GCGR激动剂减轻体重的机制，并将其与肠促胰岛素受体激动剂联合使用。机制数据目前仅在临床前啮齿动物模型中进行了评估，人类类似过程的证据有限。我们还提供了治疗方法如何改善未来肥胖治疗进展的观点。

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引用次数: 0

Potential of cyclodipeptides in combating oxidative stress in chronic diseases 环二肽在对抗慢性疾病氧化应激中的潜力。

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2026-01-01 DOI: 10.1016/j.phrs.2025.108076

Hamsaletchumi Rajan , Bey-Hing Goh , Yatinesh Kumari , Lai Ti Gew , Hooi-Leng Ser

Oxidative stress results from an imbalance between free radicals—such as reactive oxygen species (ROS) and reactive nitrogen species (RNS)—and the body’s antioxidant defenses. This imbalance contributes to the progression of diseases affecting the nervous, cardiovascular, and respiratory systems. Cyclodipeptides (CDPs) have exhibited significant antioxidant, cytoprotective, and neuroprotective properties, making them promising candidates for mitigating oxidative damage. Their ability to modulate oxidative stress pathways highlights their potential as therapeutic agents in oxidative damage-related diseases. This review discusses the role of free radicals in oxidative stress before exploring the importance of different types of CDPs in counteracting oxidative damage in various diseases.

氧化应激是由自由基（如活性氧（ROS）和活性氮（RNS））与身体抗氧化防御之间的不平衡引起的。这种不平衡导致了影响神经系统、心血管系统和呼吸系统的疾病的发展。环二肽（cyclodipeptide, CDPs）具有显著的抗氧化、细胞保护和神经保护特性，是减轻氧化损伤的有希望的候选物质。它们调节氧化应激途径的能力突出了它们作为氧化损伤相关疾病治疗剂的潜力。本文首先讨论自由基在氧化应激中的作用，然后探讨不同类型的CDPs在各种疾病中对抗氧化损伤的重要性。

引用次数: 0

Discovery, development, and characterization of potent and selective USP11 inhibitors 强效和选择性USP11抑制剂的发现、开发和表征。

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2026-01-01 DOI: 10.1016/j.phrs.2025.108075

Forum Kayastha , Noah B. Herrington , Anirban Roychowdhury , Nahid M. Nanaji , Won Sok Lee , Glen E. Kellogg , Bandish Kapadia , Ronald B. Gartenhaus

Deubiquitinases (DUBs) have long been viewed through the narrow lens of enzymatic catalysis, but emerging evidence reveals their non-catalytic domains as master regulators of oncogenic signaling. USP11, a structurally modular DUB, exemplifies this duality: beyond its canonical role in DNA repair, USP11 scaffolds key translational effectors such as eIF4B, sustaining the expression of pro-survival oncogenes in aggressive lymphomas. Here, we unveil RBF4 and RBF11, first-in-class, non-catalytic USP11 inhibitors discovered through pharmacophore-guided virtual screening anchored on the UBL domain interface. These small molecules selectively bind USP11 without disrupting its catalytic activity yet interrupt critical interactions essential for eIF4B stabilization and oncogenic translation. Mechanistically, USP11 inhibition collapses MYC-driven translational networks, destabilizes DNA repair factors, rewires calcium homeostasis, and induces a post-transcriptional apoptotic program while sparing non-malignant cells. RBF4, chemically identical to the FDA-approved anti-arrhythmic agent Dronedarone, exhibits potent antitumor efficacy in orthotopic EμMyc lymphoma models, suppressing tumor growth, metastatic spread, and ascites formation with no overt toxicity. Transcriptomic analyses reveal broad rewiring of EMT, immune, and metabolic programs, underscoring USP11’s role as a nodal regulator of tumor cell identity and plasticity. These findings establish the UBL domain of USP11 as a druggable scaffold, redefining DUBs not merely as enzymes but as structural signaling platforms. RBF4 emerges as a clinically actionable prototype for dismantling USP11-driven oncogenic circuits, illuminating a new therapeutic axis in lymphoid malignancies and beyond.

One sentence summary

Potent, selective USP11 inhibitors exhibit anti-tumor activity.

去泛素酶（DUBs）长期以来一直是通过酶催化的狭窄视角来看待的，但新出现的证据表明，它们的非催化结构域是致癌信号传导的主要调节因子。USP11是一种结构模块化的DUB，体现了这种双重性：除了在DNA修复中的典型作用外，USP11还支撑关键的翻译效应物，如eIF4B，在侵袭性淋巴瘤中维持促生存癌基因的表达。在这里，我们揭示了RBF4和RBF11，这是通过锚定在UBL结构域界面上的药物团引导虚拟筛选发现的一流的非催化USP11抑制剂。这些小分子选择性地结合USP11而不破坏其催化活性，但却中断了eIF4B稳定和致癌翻译所必需的关键相互作用。在机制上，USP11抑制破坏myc驱动的翻译网络，破坏DNA修复因子的稳定，重新连接钙稳态，并诱导转录后凋亡程序，同时保留非恶性细胞。RBF4的化学成分与fda批准的抗心律失常药物Dronedarone相同，在正位EμMyc淋巴瘤模型中显示出强大的抗肿瘤功效，抑制肿瘤生长、转移扩散和腹水形成，无明显毒性。转录组学分析揭示了EMT、免疫和代谢程序的广泛重新连接，强调了USP11作为肿瘤细胞身份和可塑性的节点调节剂的作用。这些发现确立了USP11的UBL结构域是一种可药物支架，重新定义了dub不仅是酶，而且是结构信号平台。RBF4作为一种临床可行的原型出现，用于拆除usp11驱动的致癌电路，照亮了淋巴细胞恶性肿瘤及其他肿瘤的新治疗轴。有效的、选择性的USP11抑制剂具有抗肿瘤活性。

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引用次数: 0

Advance in neuroprotective effects of proanthocyanidins (PCs): Structure, absorption, bioactivities, mechanism, and perspectives 原花青素神经保护作用的研究进展：结构、吸收、生物活性、机制及展望。

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2026-01-01 DOI: 10.1016/j.phrs.2025.108082

Yudan Zhao , Hongyuan Lu , Xiaowen Jiang

With the global population growing and aging, along with increasing environmental, metabolic, and lifestyle-related risk factors, the worldwide incidence of stroke, Alzheimer's disease (AD) and other dementias, meningitis, and other neurological disorders-along with associated mortality-has risen significantly. Proanthocyanidins (PCs), which are oligomers and polymers of flavan-3-ols, are widely distributed across the plant kingdom, including in grape seeds, cinnamon, apples, cranberries, lotus seeds, and pine bark. They represent the second most abundant class of polyphenols in nature, after lignin. A substantial body of preclinical evidence indicates that PCs exert significant neuroprotective effects through multiple mechanisms. This review provides a systematic overview of the sources, structural characteristics, and bioavailability of PCs, with a focus on their pharmacological mechanisms in nervous system disease. Specifically, it examines their roles in regulating oxidative stress, neuroinflammation, protein homeostasis, apoptosis, autophagy, and key signaling pathways, including Nrf2/HO-1, CREB/BDNF, PI3K/Akt, MAPK, and NF-κB. Furthermore, this review systematically summarized the distinct structural forms of PCs, including monomers, dimers, trimers, and polymers, and explores their structure-activity relationships (SARs) in modulating the gut-brain axis. Additionally, recent advances in PCS-based nano-delivery systems and clinical studies related to neurological disorders are summarized. Growing evidence indicates that microbial metabolism in the gut serves as a key mechanism underlying their neuroprotective effects. Finally, the potential applications of PCs as promising dietary supplements or therapeutic agents for the prevention and treatment of nervous system diseases are discussed, along with existing challenges and future perspectives.

随着全球人口的增长和老龄化，以及环境、代谢和生活方式相关风险因素的增加，世界范围内中风、阿尔茨海默病（AD）和其他痴呆、脑膜炎和其他神经系统疾病的发病率以及相关死亡率显著上升。原花青素（PCs）是黄烷-3-醇的低聚物和聚合物，广泛分布于植物界，包括葡萄籽、肉桂、苹果、蔓越莓、莲子和松树皮。它们是自然界中含量第二丰富的多酚类物质，仅次于木质素。大量临床前证据表明，pc通过多种机制发挥重要的神经保护作用。本文综述了pc的来源、结构特点和生物利用度，重点介绍了其在神经系统疾病中的药理机制。具体来说，它研究了它们在调节氧化应激、神经炎症、蛋白质稳态、细胞凋亡、自噬和关键信号通路中的作用，包括Nrf2/HO-1、CREB/BDNF、PI3K/Akt、MAPK和NF-κB。此外，本文系统地总结了pc的不同结构形式，包括单体、二聚体、三聚体和聚合物，并探讨了它们在调节肠-脑轴中的构效关系（sar）。此外，总结了基于pc的纳米递送系统的最新进展以及与神经系统疾病相关的临床研究。越来越多的证据表明，肠道中的微生物代谢是其神经保护作用的关键机制。最后，讨论了pc作为有前途的膳食补充剂或治疗药物在预防和治疗神经系统疾病方面的潜在应用，以及存在的挑战和未来的展望。

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引用次数: 0

Targeting PGC-1α axis rescues aberrant development from thyroid hormone defect in brain organoids 靶向PGC-1α轴修复类脑器官甲状腺激素缺陷的异常发育。

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2026-01-01 DOI: 10.1016/j.phrs.2025.108071

Emanuela Bottani , Francesca Ciarpella , Benedetta Lucidi , Giulia Pedrotti , Chiara Santanatoglia , Eros Rossi , Enrica Cappellozza , Elisa De Tomi , Sissi Dolci , Giovanni Malerba , Giorgio Malpeli , Ilaria Decimo

Thyroid hormone (T3) deficiency during central nervous system development leads to severe and often incurable human pathologies, including intellectual disability and motor dysfunction. Using murine dorsal forebrain organoids, we showed that T3 is required to activate mitochondrial β-oxidation and OXPHOS biogenesis to sustain neuronal development, while its absence caused profound neurodevelopmental defects such as defective maturation, astrogliosis, and reduced spontaneous activity. Mechanistically, we identified the transcriptional coactivator PGC-1α as a central mediator of the T3 effect. Pharmacological inhibition of β-oxidation in T3-supplemented organoids recapitulated the T3-deficient phenotype, whereas Ppargc1a gene augmentation rescued neuronal development under T3-deprived conditions. Most importantly, pharmacological stimulation of the PGC-1α axis with Nicotinamide Riboside or Bezafibrate rescues mitochondrial bioenergetics and neuronal development, effectively correcting aberrant brain organoid maturation despite T3 deficiency. These findings reveal for the first time the role of T3 in supporting neurodevelopment via activation of mitochondrial β-oxidation and OXPHOS biogenesis, and identify the PGC-1α axis as a promising therapeutic avenue for otherwise intractable disorders linked to thyroid hormone deficiency.

中枢神经系统发育过程中甲状腺激素（T3）缺乏导致严重且通常无法治愈的人类疾病，包括智力残疾和运动功能障碍。利用小鼠背前脑类器官，我们发现T3是激活线粒体β-氧化和OXPHOS生物发生以维持神经元发育所必需的，而缺乏T3会导致严重的神经发育缺陷，如成熟缺陷、星形胶质增生和自发活性降低。在机制上，我们确定了转录辅激活因子PGC-1α是T3效应的中心介质。在t3补充的类器官中，β-氧化的药理抑制再现了t3缺乏的表型，而Ppargc1a基因的增强则挽救了t3缺乏条件下的神经元发育。最重要的是，用烟酰胺核苷或贝扎菲特对PGC-1α轴进行药理学刺激，可以挽救线粒体生物能量和神经元发育，有效纠正T3缺乏时异常的脑类器官成熟。这些发现首次揭示了T3通过激活线粒体β-氧化和OXPHOS生物发生来支持神经发育的作用，并确定了PGC-1α轴是治疗甲状腺激素缺乏症相关顽固性疾病的有希望的治疗途径。

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引用次数: 0

Functional, synaptoproteomic and structural adaptations underlying sex-dependent traumatic stress susceptibility/resilience in the hippocampus 海马体中性别依赖性创伤应激易感性/恢复力的功能、突触蛋白质组学和结构适应。

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2026-01-01 DOI: 10.1016/j.phrs.2025.108072

Sebastiano A. Torrisi , Maria Rosaria Tropea , Silvia Rizzo , Mattia Giovenzana , Chiara Magri , Alessandro Barbon , Jessica Mingardi , Clizia Chinello , Lisa Pagani , Isabella Piga , Loredana Leggio , Nunzio Iraci , Walter Gulisano , Filippo Drago , Daniela Puzzo , Laura Musazzi , Gian Marco Leggio

Although post-traumatic stress disorder (PTSD) occurs more in women than in men, how sex influences trauma susceptibility remains largely unknown. We developed the arousal-based individual screening (AIS) model, which identifies mice as susceptible/resilient to PTSD-like phenotypes, based on changes in startle reactivity induced by 24-hour-restraint. To test the hypothesis that sex drives trauma susceptibility/resilience, we applied a multidisciplinary approach involving electrophysiological, structural, and synaptoproteomic analyses of the hippocampus in susceptible and resilient mice of both sexes. Female mice were more susceptible to the trauma than male mice and exhibited long-lasting PTSD-like phenotypes. Long-term potentiation (LTP) was impaired in hippocampal slices of both male and female susceptible mice, whereas short-term presynaptic forms of plasticity and vesicle recycling remained unchanged. Increased apical dendritic length and augmented basal dendritic spine density of pyramidal neurons were found in CA1 of male susceptible mice, while decreased dendritic length of granule neurons was uncovered in the dentate gyrus of female resilient mice. Although minor synaptoproteomic changes were observed, bioinformatic analysis suggested sex- and susceptibility/resilience-dependent profiles. Notably, several pathways involving RHO Family GTPases were found to be upregulated exclusively in susceptible male mice. Accordingly, the Rac1/Rac3 GTPases inhibitor EHop-016 rescued the hippocampal LTP impairment in susceptible male mice but not in susceptible female mice. Our findings suggest that the AIS model mirrors sex differences in PTSD susceptibility/resilience highlighting associated functional, molecular and structural alterations. This model may represent a critical first step for studying sex-dependent pathophysiological mechanisms subserving PTSD susceptibility and for sex-tailored drug development.

尽管创伤后应激障碍（PTSD）在女性中的发病率高于男性，但性别如何影响创伤易感性在很大程度上仍然未知。我们开发了基于唤醒的个体筛选（AIS）模型，该模型基于24小时约束诱导的惊吓反应变化来识别小鼠对ptsd样表型的易感性/弹性。为了验证性别驱动创伤易感性/恢复力的假设，我们采用了一种多学科方法，包括电生理、结构和突触蛋白质组学分析了易感性和恢复力小鼠的海马。雌性小鼠比雄性小鼠更容易受到创伤，并表现出持久的ptsd样表型。雄性和雌性易感小鼠海马切片的长期增强（LTP）受损，而短期突触前形式的可塑性和囊泡循环保持不变。在雄性易感小鼠CA1中发现锥体神经元的顶端树突长度增加，基底树突棘密度增加，而在雌性弹性小鼠齿状回中发现颗粒神经元树突长度减少。虽然观察到轻微的突触蛋白质组学变化，但生物信息学分析表明性别和易感性/弹性依赖谱。值得注意的是，一些涉及RHO家族gtpase的途径被发现只在易感雄性小鼠中上调。因此，Rac1/Rac3 GTPases抑制剂Ehop-016对易感雄鼠海马LTP损伤有修复作用，而对易感雌鼠无修复作用。我们的研究结果表明，AIS模型反映了PTSD易感性/恢复力的性别差异，并强调了相关的功能、分子和结构改变。该模型可能是研究PTSD易感性的性别依赖病理生理机制和性别定制药物开发的关键的第一步。

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引用次数: 0

Plasma miR-150–5p as a biomarker for immunosuppressive therapy response in acetylcholine receptor positive myasthenia gravis: a long-term prospective longitudinal study 血浆miR-150-5p作为乙酰胆碱受体阳性重症肌无力免疫抑制治疗反应的生物标志物：一项长期前瞻性纵向研究

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2026-01-01 DOI: 10.1016/j.phrs.2025.108078

Nemanja Garai , Sanja Madic , Vukan Ivanovic , Aleksa Palibrk , Jovan Pesovic , Milos Brkusanin , Ivana Basta , Stojan Peric , Dusanka Savic-Pavicevic

Insufficient effectiveness and adverse effects of immunosuppressive therapy, seen in around 20 % of acetylcholine receptor (AChR) positive myasthenia gravis (MG) patients, highlight the need for new biomarkers. MicroRNAs (miRNAs), small regulatory non-coding RNAs with tissue-specific expression, have emerged as potential biomarkers due to their abundance and accessibility in body fluids. Several miRNAs involved in immune system and drug metabolism have been associated with improvement of neuromuscular status or response to immunosuppressive therapy in AChR-positive MG patients in cross-sectional studies. Here, we explored miRNAs as plasma biomarkers for immunosuppressive therapy response in a prospective longitudinal study of newly diagnosed, drug-naïve patients. Clinical examination and plasma sampling were performed at three time points: baseline (pre-treatment), 6-month, and 12-month follow-ups. MiRNA levels were quantified by qPCR. Three out of eight analyzed miRNAs (miR-150–5p, miR-27a–3p, and miR-21–5p) showed treatment-related changes. Among them, miR-150–5p level was negatively correlated with patient functionality (MG Activities of Daily Living score – MG-ADL; p = 0.007, ρ_s=−0.433), muscle strength and weakness (Quantitative MG score – QMG; p = 0.002, ρ_s=−0.355) and overall symptoms (MG Composite score – MGC; p = 7.814e-5, ρ_s=−0.457). Pre-treatment miR-150–5p levels showed excellent prognostic ability to discriminate responders from not-responders based on achieved minimal clinical expression (AUC=0.85, p = 0.0076) and MG-ADL (AUC=0.86, p = 0.016) at 12-month follow-up. Predictive performance was also acceptable based on QMG and MGC (AUC=0.74, p = 0.001 and AUC=0.73, p = 0.0002, respectively). Our findings imply plasma miR-150–5p as a potential biomarker for predicting immunosuppressive therapy response in AChR-positive MG, suggesting its further investigation for disease monitoring and a personalized medicine approach.

大约20%的乙酰胆碱受体（AChR）阳性重症肌无力（MG）患者存在免疫抑制治疗的有效性不足和不良反应，这突出了对新的生物标志物的需求。MicroRNAs （miRNAs）是具有组织特异性表达的小调节非编码rna，由于其在体液中的丰度和可及性，已成为潜在的生物标志物。在横断面研究中，一些参与免疫系统和药物代谢的mirna与achr阳性MG患者神经肌肉状态的改善或对免疫抑制治疗的反应有关。在这里，我们在一项新诊断的drug-naïve患者的前瞻性纵向研究中探索了miRNAs作为免疫抑制治疗反应的血浆生物标志物。临床检查和血浆采样在三个时间点进行：基线（治疗前），6个月和12个月的随访。qPCR检测miRNA水平。8个分析的mirna中有3个（miR-150-5p， miR-27a-3p和miR-21-5p）显示出与治疗相关的变化。其中，miR-150-5p水平与患者功能（MG日常生活活动评分- MG- adl， p=0.007, ρs=-0.433）、肌肉力量和无力（MG定量评分- QMG， p=0.002, ρs=-0.355）、整体症状（MG综合评分- MGC， p= 7.814e-5, ρs=-0.457）呈负相关。根据12个月随访时达到的最小临床表达（AUC=0.85, p=0.0076）和MG-ADL (AUC=0.86, p=0.016)，治疗前miR-150-5p水平显示出区分应答者和无应答者的良好预后能力。基于QMG和MGC的预测性能也可以接受（AUC分别=0.74,p=0.001和AUC=0.73, p=0.0002）。我们的研究结果表明，血浆miR-150-5p是预测achr阳性MG患者免疫抑制治疗反应的潜在生物标志物，建议进一步研究其用于疾病监测和个性化医疗方法。

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引用次数: 0

Corrigendum to “Epigenetic regulation in calcific aortic valve disease: Mechanisms and therapeutic potential” [Pharmacol. Res. (2025) 223 108073] “钙化主动脉瓣疾病的表观遗传调控：机制和治疗潜力”的勘误表[Pharmacol]。Res.(2025) 223 108073]。

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2026-01-01 DOI: 10.1016/j.phrs.2025.108083

Hanshen Luo, Yuehang Yang, Chiyang Xie, Chuli Shi, Siyuan Liu, Jiawei Shi

引用次数: 0

Corrigendum to “Tagitinin F has anti-inflammatory, anti-nociceptive and anti-matrix metalloproteinase properties: An in silico, in vitro and in vivo study” [Pharmacol. Res. 164 (2021) 105303] “他吉宁F具有抗炎、抗伤害和抗基质金属蛋白酶特性：一项硅、体外和体内研究”的勘误表[Pharmacol]。Res. 164(2021)[105303]。

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2026-01-01 DOI: 10.1016/j.phrs.2025.108070

Laíla Pereira Silva , Eliziária Cardoso Santos , Bruno Arantes Borges , Marcia Paranho Veloso , Daniela Aparecida Chagas-Paula , Reggiani Vilela Gonçalves , Rômulo Dias Novaes

引用次数: 0

Mitochondrial pyruvate dehydrogenase kinase 1 drives bevacizumab resistance and malignant phenotype of TNBC by enhancing mitophagy 线粒体丙酮酸脱氢酶激酶1通过增强线粒体自噬驱动TNBC的贝伐单抗耐药和恶性表型。

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-12-31 DOI: 10.1016/j.phrs.2025.108081

Yan Ye , Qian Zeng , Zuli Ou , Xiaoqian Ju , Qingyu Liao , Canling Li , Dian Zhang , Yu Wei , Xiang Zhang , Kejia Wu , Tingmei Chen

Bevacizumab is an anti-angiogenic agent widely used in neoadjuvant chemotherapy for advanced triple-negative breast cancer (TNBC). TNBC patients frequently acquire resistance to bevacizumab due to the hypoxic tumor microenvironment, yet the underlying molecular mechanism remains unclear. Here, we demonstrate that mitochondrial reprogramming under hypoxia is crucial for resistance to bevacizumab. Mechanically, prolonged hypoxia causes the glycolytic pathway enzyme PDK1 to accumulate inside mitochondria. In mitochondria, PDK1 exerts its non-canonical function to phosphorylate mitochondrial protein Prohibitin 2 (PHB2) at Ser190. Phosphorylation at Ser190 stabilizes PHB2 and enhances its binding with LC3, thereby initiating mitophagy. Functionally, mitochondrial PDK1 (mito-PDK1) initiates mitophagy in response to hypoxia-induced mitochondrial damage and promotes the malignant phenotype of TNBC cells. In xenograft tumors, inhibiting the function of mito-PDK1 enhances the sensitivity to bevacizumab. Collectively, our findings identify the crucial function and mechanism of mito-PDK1 in TNBC. Targeting mito-PDK1 function may emerge as a novel therapeutic strategy to address acquired resistance to bevacizumab.

贝伐单抗是一种抗血管生成药物，广泛用于晚期三阴性乳腺癌（TNBC）的新辅助化疗。由于肿瘤微环境缺氧，TNBC患者经常获得对贝伐单抗的耐药，但其潜在的分子机制尚不清楚。在这里，我们证明了缺氧条件下线粒体重编程对贝伐单抗耐药性至关重要。机械上，长时间的缺氧导致糖酵解途径酶PDK1在线粒体内积聚。在线粒体中，PDK1发挥其非规范功能，使线粒体蛋白禁止蛋白2 （PHB2）在Ser190位点磷酸化。Ser190磷酸化稳定PHB2并增强其与LC3的结合，从而启动有丝分裂。在功能上，线粒体PDK1 （mito-PDK1）启动线粒体自噬以应对缺氧诱导的线粒体损伤，并促进TNBC细胞的恶性表型。在异种移植物肿瘤中，抑制mitto - pdk1的功能可增强对贝伐单抗的敏感性。总的来说，我们的研究结果确定了mito-PDK1在TNBC中的关键功能和机制。靶向mitto - pdk1功能可能成为解决贝伐单抗获得性耐药的新治疗策略。

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引用次数: 0